The emerging light-based imaging technique of acoustic-resolution photoacoustic endomicroscopy (AR- PAEM) enables visualization of subsurface tissues with microscopic resolution, at depths of many millimeters. AR-PAEM images provide crucial information regarding microvasculature, morphology, and tissue physiology (blood oxygenation). For cancers originating in the epithelial tissues (e.g. oral cavity and pharynx, and the digestive, respiratory, genital, and urinary systems) PAEM offers the potential to detect the very earliest mucosal changes at the microstructural, biochemical, and molecular levels by presenting subsurface tissue morphologic, physiologic, and cellular features. This provides valuable information regarding cancer onset, progression, and response of to therapy. Key to AR-PAEM is the use of short-duration (nanosecond) laser pulses at specific wavelengths. Wavelength-selective absorption by targeted tissues gives rise to a primary acoustic signal. High-resolution acoustic imaging is achieved by means advanced acoustic detectors and associated signal processing electronics and software. Tissue discrimination is obtained from differential images at multiple (deep red and near infrared) wavelengths. The goals of the proposed program are to develop an advanced diode-pumped alexandrite laser source for clinical AR-PAEM, and to demonstrate its performance for bladder cancer screening and diagnostics. The laser will have specialized features for achieving the imaging depth, functional imaging accuracy, and image acquisition time required for clinical bladder cancer screening. In this Phase I program we will develop a clinical prototype laser source providing features critical for clinical AR-PAEM cancer screening and diagnostics. The laser will be integrated into an AR-PAEM imaging system developed by the University of Michigan. Pre-clinical imaging studies on animal models will be performed to evaluate the benefits of the laser technology - a variety of image parameters will be quantified, such as imaging depth, imaging speed, contrast, resolution, and blood oxygenation. This will provide an assessment of the benefits of the laser system for AR-PAEM, and will provide guidance for the development of a clinical pilot laser system in Phase II.